Submissions for variant NM_000051.4(ATM):c.3576G>C (p.Lys1192Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002455039	SCV002613273	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-02	criteria provided, single submitter	clinical testing	The p.K1192N variant (also known as c.3576G>C), located in coding exon 23 of the ATM gene, results from a G to C substitution at nucleotide position 3576. The amino acid change results in lysine to asparagine at codon 1192, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. Another alteration impacting the same nucleotide position (c.3576G>A) has been described in individuals with a clinical diagnosis of ataxia telangiectasia, and has been observed in the homozygous state in individuals with severe disease (Telatar M et al. Am J Hum Genet, 1998 Jan;62:86-97; Gilad S et al. Am J Hum Genet, 1998 Mar;62:551-61; Sandoval N et al. Hum Mol Genet, 1999 Jan;8:69-79). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775669	SCV004680207	likely pathogenic	Ataxia-telangiectasia syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1192 of the ATM protein (p.Lys1192Asn). This variant also falls at the last nucleotide of exon 24, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1732830). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.3576G nucleotide in the ATM gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8845835, 9887333, 19691550, 22071889, 27599564). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.